A major cause of Congestive Heart Failure (CHF) in the Western Hemisphere is chronic chagasic cardiomyopathy, which is due to infection by the parasite Trypanosoma cruzi. About 30% of infected individuals develop the cardiac form of the disease, usually decades after the primary infection. Cardiac chagasic patients present cardiomegaly, electrical and mechanical disturbances of heart function. The disease evolutes to congestive heart failure and the only currently available therapy is heart transplantation. Performing heart transplants in chagasic patients is not only expensive, but also problematic, as immunosuppressive drugs can bring about patient parasitemia due to persistent parasitism in the chronic phase of infection. Supported by NIH funding during initial RO1 award, we have tested efficacy of an alternative therapeutic procedure in a mouse model of chronic chagasic cardiomyopathy (CCC), based on transplantation of the mononuclear fraction of the bone marrow (BMCs). Quantification of heart inflammatory foci and degree of fibrosis using confocal microscopy and morphometric analysis, as well as functional and structural analysis through MRI, electro- and echocardiography, and array analysis of gene expression in treated vs. infected mice all indicate that BMC is a very effective treatment that both prevents disease progression and restores cardiac function. These studies, and human clinical trials underway, raise issues regarding whether other cell types might be even more efficacious, and also raise the question of whether improvement is due to paracrine action of the stem cells or to direct engraftment. This application, from a consortium of senior investigators and collaborators with expertise in all aspects of the proposed studies will compare alternative sources of stem cells for treatment of CCC in the mouse model and will use both cell culture and in vivo strategies to test hypotheses regarding mechanisms of stem cell-based improvement in CCC. These experiments are expected to provide new insights into most effective stem cell treatments for CHF and also into basic mechanisms of stem cell biology and stem cell therapy. RELEVENCE: Chronic chagasic cardiomyopathy is a debilitating disease manifested by CHF, arrhythmias and embolic events. It is a devastating disease with a great economic and social burden in endemic areas of the world. There is no cure and heart transplantation, with all of its complications, is often the only life-saving remedy. Chagas disease is now recognized more frequently in the United States because of increased immigration. Stem cell transplantation provides a new and exciting modality in the management of patients with chronic chagasic cardiomyopathy. The experimental studies detailed in this application will provide valuable basic information required for the clinical trials that are both planned and already underway in Brazil.